Dihydropyrrolo-pyridines



Jill

United States Patent DIHYDROPYRROLO-PYRIDINES William B. Wright, Jr., Plainfield, N. J., assignor to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application December 31, 1953, Serial No. 401,724

7 Claims. (Cl. 260-295) in which R is hydrogen or a lower alkyl, carbalkoxy, acyl, aroyl or benzenesulfonyl radical, R is a halogen, hydroxy, alkoxy, amino or substituted amino radical, salts and quaternary salts thereof.

' In general, the bases are soluble in alcohol, usually relatively insoluble in ether and may be Water soluble, depending upon molecular size and constituents. The hydrochloride salts are generally water soluble but reprecipitated by excess hydrochloric acid or alcohol. Most are essentially alcohol insoluble. The salts may usually be recrystallized from aqueous alcohol mixtures. The solubility of both the salts and the bases is low in many organic solvents including ether.

The preparation of these compounds is dependent upon the particular compound desired. For example, 7-amino- 2,3-dihydro-6-methyl-lH-pyrrolo[3,4-clpyridine is prepared from the gamma-lactam of B-amino-S-aminomethyl- Z-methylpyridine-4-carboxylic acid by a lithium aluminum hydride reduction. Having obtained the above compound, the derivatives thereof in which R of the general formula is benzoyl or carbethoxycan be obtained by reaction with the corresponding acid chloride under alkaline conditions. When R contains the above radicals and R is an amino group the compounds can be converted through the diazo derivatives to a variety of compounds substituted in the 7- position by, for example, hydroxy, alkoxyl, mercapto or halogen atoms. Removal of the radical R by acid or alkaline hydrolysis liberates a new group of compounds of the present invention.

In preparing the compounds wherein R" and R are acyl and acylamino respectively, 7-amino-2,3-dihydro-6 methyl-lH-pyrrolo-[3,4-clpyridine is reacted with an alkanoic acid anhydride. These compounds can be converted into'the corresponding alkyl compounds by reduction of the acyl groups with lithium aluminum hydride.

The compounds of the present invention, as illustrated by the general formula, can be those in which R is hydrogen, methyl, ethyl, propyl, butyl, carbomethoxy, carbe'thoxy, carbopropoxy, carbobutoxy, acetyl, propionyl,

2, butyryl, benzoyl, naphthoyl, p-aminobenzenesulfonyl, maminobenzenesulfonyl, and the like. The radical R" can be hydroxyl, methoxy, ethoxy, propoxy, butoxy, amino, acetylamino, propionylamino, butyrylamino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, and the like.

The preparation of representative dihydropyrrolo- [3,4-clpyridine compounds of the present invention is described in the following examples. Temperatures are expressed in degree centigrade.

EXAMPLE 1 7-amino-2,3-dihydro-6-methyl-l H -pyrr0lo [3,4-c] pyridine A solution of one part of the gamma-lactam of 3- amino-S-aminoethyl-2-methylpyridine-4-carboxylic acid in 200 parts by volume of tetrahydrofuran is added over a 30-minute period at 45 -50 to a solution of 2 parts of lithium aluminum hydride in parts by volume of tetrahydrofuran. The reaction is heated at 60-65 for 7 hours and then excess lithium aluminum hydride and complex salts are decomposed by the addition of 4 parts of water in 15 parts by volume of tetrahydrofuran. The reaction is filtered at 60 and the cake washed with a little ethanol. The filtrate is acidified with concentrated hydrochloric acid and on standing deposits 0.77 part of a brown powder. When this material is dissolved in water, clarified and treated with concentrated hydrochloric acid, 7-amino-2,3-dihydro-6-methyl-lH-pyrrolo- [3,4-clpyridine dihydrochloride precipitates as an almost white powder.

The free base, melting at 167-9 0., is obtained by treating the dihydrochloride with alcoholic sodium methylate, filtering off the salt and concentrating the filtrate. 1

EXAMPLE 2 7-aminq-Z-benzoyl-2,3-dihydro-6-methyZ-l H pyrrolo [3,4-c] pyridine Benzoyl chloride, 165 parts, is added over a 40-minute period at 30-35 to a mixture of 280 parts of 7-amino- 2,3-dihydro-6-methyl-lH-pyrrolo[3,4-clpyridine dihydrochloride and parts of sodium hydroxide in 2400 parts of water. The reaction is stirred for two hours longer at 3035 and then filtered and washed with water. After drying in the oven it is recrystallized from ethanol and 7-amino-2-benzoyl-2,3-dihydro-6-methyl-lH-pyrrolo- [3,4-c]pyridine, melting at 202-3 is obtained in 61% yield.

EXAMPLE 3 7-amzno-2-carbethoxy-2,3-dihydr0-6-methyl-1H- pyrr olo [3,4-0] pyridine 5 N Sodium hydroxide, 400 parts, and 194 parts by volume of ethyl chloroformate are added simultaneously to a solution of 448 parts of 7-amino-2,3-dihydro-6- methyl-lH-pyrrolo[3,4-clpyridine dihydrochloride, 1500 parts of Water and 800 parts by volume of 5 N sodium hydroxide. The reaction is held at l020 during this addition and water is added as required to thin the thick slurry which forms. The reaction is stirred for one and one-half hours and the product is then filtered and washed with water. The wet cake is dissolved'in a minimum of boiling alcohol, treated with activated charcoal and cooled. 7-amino-2-carbethoxy-2,3-dihydro-6-methyl-1H pyrrolo- [3,4-c] pyridine is obtained in 65% yield as a monohydrate melting at l823 C.

EXAMPLE 4 7-acetamido-2-acetyl-2,3-dihydr0-6-methyl-1 H pyrrolo [3,4-c] pyridine Acetic anhydride, 300 parts by volume, is heated to 80 and 97 parts of 7-amino-2,3-dihydro-6-methyl-lH-pyrrolo- [3,4-clpyridine base is added in portions. After the 'exothermic reaction subsides the mixture is heated on the steam bath for. one andone-half hours longer and :then concentratedto dryness. The product is recrystallized from ethanol. The yield of "pure '7-acetamido-2- acetyl-Z3-dihydro-6 methyl-1H pyrrolo[3, r c]pyridine,

melting at 2257 C., is 73%.

EXAMPLE 5 2,3 dihydro-2-ethyl-7-ethy[amino-641iethyl-1H- pyrrolo [3,4-c] pyridine dihydroch lo ride acid and the white precipitate is filtered. On recrystallization from alcohol, pure 2,3-dihydro-2-ethyl-7-ethylamino 6 methyl 1H -pyrrolo[3,'4-c] pyridine dihydrochloride is obtained. 7

EXAMPLE 6 Z-benzoyl-Zfl -dihydr0-7-hydr0xy 6-methyl-1 H pyrr0lo[3,4-c] pyridine hydrochloride A solution of 21 parts of sodium nitrite'in 100 parts 4 7 under reduced pressure to a small volume, diluted with water and again concentrated until precipitation occurs.

The precipitate is filtered, water washed, dissolved in 1 dilute acid, treated with activated charcoal to remove color and the pH adjusted with sodium carbonate to 5.2. The product is filtered .and dried. After recrystallizing first from ethanol and then fr'omisopropyl acetate, 2- benzoyl-2,3-dihydro-7-methoxy-6 methyl 1H pyrrolo- [3,4-clpyridine, melting at 149 151' C., is obtained in yield. a

' EXAMPLE'IO 2,3-dihydr0-7-methaw-6 m:thyl-I H -pyrroloe [3,4-c] pyridine'dihydrochloride When the compound of Example 9 is heated on the steam bath with aqueous alcoholic sodium hydroxide and then. acidified, 2,3-dihydro-7-methoxy-6-methyl-lH-pyrro1o[3,4-c] pyridine dihydroehloride isobtained in 74% yield.

EXAMPLE .11

7-methoxy-2-acetyl-2,3-dihydro-6-methyl-1H- pyrrol0[3,4-c] pyridine When 2,3-dihydro-7-methoxy-6 methyl 1H pyrrolo- [3,4-c1pyridine is heated on the steam bath'for one and one-half hours with acetic anhydride, an 81% crude of water is added over a 30-minute period at 24 to a mixture of 76 parts'of 7-amino-2-benzoyl-2,3-dihydro-6 methyl-ll-i-pyrrolo[3,4-clpyridine dihydrochloride, 3500 parts of water and 240-parts by volumeof 5N hydrochloric acid. The reaction isgradually warmed over a two hour period to- 28 and 'then' 80-parts by volume of 5N sodium hydroxide is added. The reaction is concentrated under reduced pressure; filtered and washed with acetone. 7 On recrystallization from ethanol, 2- benzoyl-Z,3-dihydro-7rhydroxy-6 methyl 1H pyrrolo- [3,4-clpyridine hydrochloride, melting at 222-4 C., is obtained in 59% yield.

EXAMPLE 7 2 ,3-dihydro-7-hydr0x3 -6-methylfl H -pyrr0l0- [3,4-c] pyridine dihydrochloride When'the compound of Example 6 is heated on the steam bath with 10 parts byvolume of 5N hydrochloric acid for 3-5 'hours, 2,3-dihydro-7-hydroxy-6-methyl-1H- pyrrolo[3,4-c]pyridine dihydrochloride is obtained in nearly quantitative yield.

EXAMPLE 8 2-carbeth1oxy-2,3-dihydr0-7-hydr0xy-6-methyl- 1H-pyrr0l0[3,4-cl pyridine hydrochloride When 7-amino-2-carbethoxy-2,3-dihydro 6rnethyl-1H- pyrrolo[3,4-c]pyridine is treated with sodium nitrite by essentially the same procedure 'as in Example 6, Z-carbethoxy-2,3-dihydro-7-hydroxy-6 methyl 1H pyrrolo- [3,4-c1pyridine hydrochloride, melting at 246 C., is obtained in 69% yield;

' EXAMPLE 9 V 2 -benz0yl-2 ,3-dihydro-7 methoxyrd-methyl-l H pyrrolo[3,4-c]pyridine 7 A solution of'56 parts of .sodiumnitrite in 160 parts 1 of water is added over a one hour periodat 48-.50 C. to a mixture of 101 parts of 7-amino2-benzoyl-2,3- dihydro-6-methyl-lH-pyrrolo[3,4-clpyridine, 4000 parts by volume of methanol and 166 parts by volume of concentrated hydrochloric acid. The reaction isheated for one hour longer 'andthenadjusted to .a pH of about 7 with sodium carbonate. The .reaction is concentrated yield of 7-methoxy-2-acetyl-2,3-dihydro 6-methyl-1H- pyrrolo[3,4-c]pyridine is obtained. Pure material melting at 116117 is obtained'by recrystallizing this from ethanol. I a V EXAMPLE'IZ 7-meth oxy-Z-acety Z-2,3-dihyd'r0-6-m ethyl-1H- pyrr0lo[3,4-c] pyridine methiodide A mixture of 2.06 parts of 7-methoxy-2-acetyl-2,3- dihydro-6-methyl-lHapyrrolo[-3,4-c]pyridine, 1.87 parts by volume of methyl iodide, and-15 parts by volume of ethanol is allowed to stand at'room temperature forfive days. It is then heated at refluxing temper'atures forone and'oneehalf hours and concentrated under reduced pressure. Upon addition of ethy1,ether.;3.1 g.'1of;7:methoxy-- 2-acetyl-2,3 dihydro -'6 methyl 1H -:pyrrolo.[-3j4-:c]- pyridine methiodide,"meltingat .17'5177., is "obtained.

EXAMPLE 13 7 methoxy-Z-actyl-2,3-dihydro -6 methylEIH- f pyrr0lo[3,4-c] pyridine ethiodide By substituting ethyl iodide for methyl iodide inthe procedure of Example 12, 7-methoxy-2-acetylr2g3-dihy dro-6-methyl-1H-pyrrolo[3,4-clpyridine ethiodide, .melting at l75,'may be obtained. I

EXAMPLE .14

A mixture of 7-hydroxy.-2,3-d.ihydro-6methyl lH- pyrrol0[3,4-c]pyridine. and acetic anhydride is heated on the steam bath for one and one-halfhours andthenconcentrated under reduced pressure. The product i s crystallized and washed out of the flask with a little ethanol. Upon recrystallization from alcohol ,pure 7'-ace tox y-2 acetyl 2,3 dihydro 6 methyl 1H -pyrrolo [3,4- clpyridine, meltingat 1434, is obtained EXAMPL .15 1

This compound melting at ;2224 is' obtained v:by'reacting 7 acetoxy-Z-acetyl-Z,3-dihydro-6-methyl:lHEpyrrolo [3,452] pyridine with. methyl. iodidezas inExampie .12.

EXAMPLE 16 7-i0d0-2-carbethoxy-Z,3-dihydro-6-methyl-1H-pyrrolo [3,4-] pyridine A mixture of 9.56 parts of 7-amino-2-carbethoxy-2,3- dihydro-6-methyl-1H-pyrrolo[3,4-c]pyridine, 250 parts of water and 48 parts by volume of N sulfuric acid is cooled to 0 C. and a solution of 2.94 parts of sodium nitrite in parts of water is added. The reaction is stirred at a maximum temperature of 2 C. for ten minutes longer and a solution of 7.3 parts of potassium iodide in parts of water is added. The reaction is allowed to gradually warm up to room temperature and then filtered to remove some brown insoluble material. Treatment of the filtrate with sodium bicarbonate caused crude 7-iodo-2-carbethoxy 2,3 dihydro-6-methyl-1I-I- pyrrolo[3,4-clpyridine to separate. A pure product of melting point 133-4 is obtained by recrystallizing from ethanol.

EXAMPLE 17 7-br0mO-Z-carbethOxy-Z,3-dihya'r0-6-methyl-1H-pyrrolo [3 ,4-cl pyridine A mixture of 9.56 parts of 7-amino-2-carbethoxy-2,3- dihydro-6-methyl-lH-pyrrolo[3,4-clpyridine, 250 parts of water and parts by volume of 48% hydrogen bromide was cooled to 0 C. and a solution of 2.9 parts of sodium nitrite in 20 parts of water was added. The reaction was held at 0 to 4 for a total of 25 minutes and then poured into a solution of seven parts of cuprous bromide in 15 parts of water and 25 parts of 48% hydrogen bromide. The mixture was allowed to stand for an hour, heated to 55 C., clarified with activated charcoal and cooled. Hydrogen sulfide gas was passed in and the dark precipitate which formed was filtered. The filtrate was treated with sodium bicarbonate and 7 bromo-2-carbethoxy-2,3-dihydro-6-methyl-lH-pyrrolo [3,4-clpyridine precipitated. On recrystallization from ether, a pure product melting at 956 is obtained.

EXAMPLE 18 2- (p-acetamidobenzenesulfonyl) 2,3-dihydr0-7-meth0xy- 6-methyl-1H-pyrrol0 [3,4-c] pyridine A mixture of 1.19 parts of 2,3-dihydro-7-methoxy-6- methyl-lH-pyrrolo[3,4-clpyridine dihydrochloride, 1.23 parts of p-acetamidobenzenesulfonyl chloride and parts of 1N sodium hydroxide was stirred at 30-35 for one hour and then heated on the steam bath for two hours. The precipitate was filtered, water washed and oven dried. It was then recrystallized from ethanol for pure 2 (p acetamidobenzenesulfonyl) 2,3 dihydro-7- methoxy-6-methy1-1H-pyrrolo[3,4-c] pyridine melting at 212-213 d.

EXAMPLE 19 2-(p-aminobenzenesulfonyl) -2,3-dihydro-7-methoxy- 6-methyl-1H-pyrrolo [3,4-c] pyridine When the compound of Example 18 is heated on the steam bath with aqueous alcoholic sodium hydroxide, 2 (p aminobenzenesulfonyl)-2,3-dihydro-7-methoxy-6- methyl-lH-pyrrolo[3,4-clpyridine is obtained.

EXAMPLE 20 2-(p-acetamidobenzenesulfonyl)-7amino-2,3-dihydro- 6-methyl-1H-pyrrol0 [3,4-cl pyridine A mixture of 448 parts of 7-amino-2,3-dihydro-6- methyl-1H-pyrrolo[3,4-clpyridine dihydrochloride, 490 parts of p-acetamidobenzenesulfonyl chloride, 3500 parts of Water and 256 parts of sodium hydroxide is stirred for three hours and then heated on the steam bath for one hour. The insoluble portion is filtered ofl, water washed, and oven dried. The crude yield is On recrystallization from ethanol pure 2-(p-acetamidobenzenesulfonyl)-7-amido-2,3-dihydro 6 methyl 1H- pyrrolo[3,4-c]pyridine is obtained as a half-hydrate.

EXAMPLE 21 2- (p-acetaniiaoberzzenesulfonyl) -7-hydroxy-2,3dihydr0- 6-methyl-1H-pyrr0lo [3,4-0] pyridine The above compound is prepared in 35% yield by treating 7-hydroxy-2,3-dihydro 6 methyl-lH-pyrrolo [3,4-clpyridine with p-acetamidobenzenesulfonyl chloride in a procedure similar to that used in Example 20.

I claim:

1. Compounds of the group consisting of those having the formula CH N References Cited in the file of this patent Chem. Abst. 45 :8530a. 

1. COMPOUNDS OF THE GROUP CONSISTING OF THOSE HAVING THE FORMULA 